6 results on '"Jean J. Zhao"'
Search Results
2. Lactate regulates cell cycle by remodelling the anaphase promoting complex
- Author
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Weihai Liu, Yun Wang, Luiz H. M. Bozi, Patrick D. Fischer, Mark P. Jedrychowski, Haopeng Xiao, Tao Wu, Narek Darabedian, Xiadi He, Evanna L. Mills, Nils Burger, Sanghee Shin, Anita Reddy, Hans-Georg Sprenger, Nhien Tran, Sally Winther, Stephen M. Hinshaw, Jingnan Shen, Hyuk-Soo Seo, Kijun Song, Andrew Z. Xu, Luke Sebastian, Jean J. Zhao, Sirano Dhe-Paganon, Jianwei Che, Steven P. Gygi, Haribabu Arthanari, and Edward T. Chouchani
- Subjects
Multidisciplinary - Published
- 2023
3. Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma
- Author
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Jean J. Zhao, Humsa S. Venkatesh, Craig J. Thomas, Jing Ni, Patrick J. Morris, Damien Y. Duveau, Shawn M. Gillespie, Surya Nagaraja, James Lennon, Pamelyn Woo, Lydia T. Tam, and Michelle Monje
- Subjects
Adult ,Male ,0301 basic medicine ,Cell Adhesion Molecules, Neuronal ,ADAM10 ,Nerve Tissue Proteins ,Neuroligin ,Biology ,ADAM10 Protein ,Mice ,Phosphatidylinositol 3-Kinases ,03 medical and health sciences ,Downregulation and upregulation ,Glioma ,Tumor Microenvironment ,medicine ,Animals ,Humans ,Secretion ,Child ,Cell Proliferation ,Mice, Knockout ,Neurons ,Tumor microenvironment ,Multidisciplinary ,Brain Neoplasms ,Cell adhesion molecule ,TOR Serine-Threonine Kinases ,Membrane Proteins ,medicine.disease ,nervous system diseases ,Oligodendroglia ,030104 developmental biology ,Focal Adhesion Protein-Tyrosine Kinases ,Immunology ,Cancer research ,Heterografts ,Amyloid Precursor Protein Secretases ,Signal transduction ,Neoplasm Transplantation ,Signal Transduction - Abstract
High-grade gliomas (HGG) are a devastating group of cancers, and represent the leading cause of brain tumour-related death in both children and adults. Therapies aimed at mechanisms intrinsic to glioma cells have translated to only limited success; effective therapeutic strategies will need also to target elements of the tumour microenvironment that promote glioma progression. Neuronal activity promotes the growth of a range of molecularly and clinically distinct HGG types, including adult and paediatric glioblastoma (GBM), anaplastic oligodendroglioma, and diffuse intrinsic pontine glioma (DIPG). An important mechanism that mediates this neural regulation of brain cancer is activity-dependent cleavage and secretion of the synaptic adhesion molecule neuroligin-3 (NLGN3), which promotes glioma proliferation through the PI3K-mTOR pathway. However, the necessity of NLGN3 for glioma growth, the proteolytic mechanism of NLGN3 secretion, and the further molecular consequences of NLGN3 secretion in glioma cells remain unknown. Here we show that HGG growth depends on microenvironmental NLGN3, identify signalling cascades downstream of NLGN3 binding in glioma, and determine a therapeutically targetable mechanism of secretion. Patient-derived orthotopic xenografts of paediatric GBM, DIPG and adult GBM fail to grow in Nlgn3 knockout mice. NLGN3 stimulates several oncogenic pathways, such as early focal adhesion kinase activation upstream of PI3K-mTOR, and induces transcriptional changes that include upregulation of several synapse-related genes in glioma cells. NLGN3 is cleaved from both neurons and oligodendrocyte precursor cells via the ADAM10 sheddase. ADAM10 inhibitors prevent the release of NLGN3 into the tumour microenvironment and robustly block HGG xenograft growth. This work defines a promising strategy for targeting NLGN3 secretion, which could prove transformative for HGG therapy.
- Published
- 2017
4. CDK4/6 inhibition triggers anti-tumour immunity
- Author
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Jaclyn Sceneay, Susanne Ramm, Jeremy Hoog, Thomas M. Roberts, Otto Metzger-Filho, Sandra S. McAllister, Matthew J. Ellis, Ian E. Krop, Hye-Jung Kim, April C. Watt, Molly J. DeCristo, Naveed Khan, Jessalyn M. Ubellacker, Jean J. Zhao, Eric P. Winer, Ben Li, Haley BrinJones, Shom Goel, Shaozhen Xie, and Cynthia X. Ma
- Subjects
0301 basic medicine ,Cell cycle checkpoint ,Cell ,Breast Neoplasms ,Biology ,T-Lymphocytes, Regulatory ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Neoplasms ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Cytotoxic T cell ,Phosphorylation ,Protein Kinase Inhibitors ,Cell Proliferation ,RNA, Double-Stranded ,Antigen Presentation ,Multidisciplinary ,Biological Mimicry ,Cell Cycle ,Cyclin-Dependent Kinase 4 ,Cell Cycle Checkpoints ,Cyclin-Dependent Kinase 6 ,Cell cycle ,Immune checkpoint ,3. Good health ,Cell biology ,Repressor Proteins ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Viruses ,Cancer research ,Female ,Interferons ,CDK4/6 Inhibition ,Transcriptome ,G1 phase ,Cell Division ,Signal Transduction - Abstract
Cyclin-dependent kinases 4 and 6 (CDK4/6) are fundamental drivers of the cell cycle and are required for the initiation and progression of various malignancies. Pharmacological inhibitors of CDK4/6 have shown significant activity against several solid tumours. Their primary mechanism of action is thought to be the inhibition of phosphorylation of the retinoblastoma tumour suppressor, inducing G1 cell cycle arrest in tumour cells. Here we use mouse models of breast carcinoma and other solid tumours to show that selective CDK4/6 inhibitors not only induce tumour cell cycle arrest, but also promote anti-tumour immunity. We confirm this phenomenon through transcriptomic analysis of serial biopsies from a clinical trial of CDK4/6 inhibitor treatment for breast cancer. The enhanced anti-tumour immune response has two underpinnings. First, CDK4/6 inhibitors activate tumour cell expression of endogenous retroviral elements, thus increasing intracellular levels of double-stranded RNA. This in turn stimulates production of type III interferons and hence enhances tumour antigen presentation. Second, CDK4/6 inhibitors markedly suppress the proliferation of regulatory T cells. Mechanistically, the effects of CDK4/6 inhibitors both on tumour cells and on regulatory T cells are associated with reduced activity of the E2F target, DNA methyltransferase 1. Ultimately, these events promote cytotoxic T-cell-mediated clearance of tumour cells, which is further enhanced by the addition of immune checkpoint blockade. Our findings indicate that CDK4/6 inhibitors increase tumour immunogenicity and provide a rationale for new combination regimens comprising CDK4/6 inhibitors and immunotherapies as anti-cancer treatment.
- Published
- 2017
5. Essential roles of PI(3)K–p110β in cell growth, metabolism and tumorigenesis
- Author
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Sen Zhang, Pixu Liu, Sabina Signoretti, Sang Hyun Lee, Thomas M. Roberts, Shidong Jia, Jing Zhang, Massimo Loda, Zhenning Liu, Lei Zhang, and Jean J. Zhao
- Subjects
Male ,medicine.medical_specialty ,Proto-Oncogene Proteins c-akt ,Biology ,Article ,Mice ,Phosphatidylinositol 3-Kinases ,Epidermal growth factor ,Internal medicine ,Glucose Intolerance ,medicine ,Animals ,Homeostasis ,Humans ,Insulin ,Phosphorylation ,Kinase activity ,Protein kinase B ,Cell Proliferation ,Multidisciplinary ,Epidermal Growth Factor ,Kinase ,PTEN Phosphohydrolase ,Prostatic Neoplasms ,Fibroblasts ,Cell biology ,Mice, Inbred C57BL ,Cell Transformation, Neoplastic ,Glucose ,Endocrinology ,Liver ,Second messenger system ,Insulin Resistance ,Signal transduction ,Signal Transduction - Abstract
On activation by receptors, the ubiquitously expressed class IA isoforms (p110alpha and p110beta) of phosphatidylinositol-3-OH kinase (PI(3)K) generate lipid second messengers, which initiate multiple signal transduction cascades. Recent studies have demonstrated specific functions for p110alpha in growth factor and insulin signalling. To probe for distinct functions of p110beta, we constructed conditional knockout mice. Here we show that ablation of p110beta in the livers of the resulting mice leads to impaired insulin sensitivity and glucose homeostasis, while having little effect on phosphorylation of Akt, suggesting the involvement of a kinase-independent role of p110beta in insulin metabolic action. Using established mouse embryonic fibroblasts, we found that removal of p110beta also had little effect on Akt phosphorylation in response to stimulation by insulin and epidermal growth factor, but resulted in retarded cell proliferation. Reconstitution of p110beta-null cells with a wild-type or kinase-dead allele of p110beta demonstrated that p110beta possesses kinase-independent functions in regulating cell proliferation and trafficking. However, the kinase activity of p110beta was required for G-protein-coupled receptor signalling triggered by lysophosphatidic acid and had a function in oncogenic transformation. Most strikingly, in an animal model of prostate tumour formation induced by Pten loss, ablation of p110beta (also known as Pik3cb), but not that of p110alpha (also known as Pik3ca), impeded tumorigenesis with a concomitant diminution of Akt phosphorylation. Taken together, our findings demonstrate both kinase-dependent and kinase-independent functions for p110beta, and strongly indicate the kinase-dependent functions of p110beta as a promising target in cancer therapy.
- Published
- 2008
6. Correction: Corrigendum: Essential roles of PI(3)K–p110β in cell growth, metabolism and tumorigenesis
- Author
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Sang Hyun Lee, Massimo Loda, Jean J. Zhao, Thomas M. Roberts, Lei Zhang, Pixu Liu, Zhenning Liu, Sabina Signoretti, Sen Zhang, Shidong Jia, and Jing Zhang
- Subjects
0301 basic medicine ,Multidisciplinary ,business.industry ,Cancer ,Metabolism ,P110α ,Biology ,Bioinformatics ,medicine.disease ,medicine.disease_cause ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Text mining ,Prostate ,030220 oncology & carcinogenesis ,Pi ,medicine ,Cancer research ,Carcinogenesis ,business - Abstract
Nature 454, 776–779 (2008); doi:10.1038/nature07091 In Fig. 3b of this Letter we inadvertently used the wrong images (partial duplicates of images representing p110α−/− mice) in the panels representing p110β−/− mice. The corrected Fig. 3b is shown in Fig. 1 of this Corrigendum. The conclusions of the paper are not affected; knocking out either p110α or p110β does not affect the growth of the normal prostate.
- Published
- 2016
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